Charged particle beams, such as protons, are advantageous for cancer therapy because the finite range of the particles results in relatively little dose at the surface of a patient's body while depositing greater dose just before the particles come to rest in tissue (the Bragg peak). Because of this dose distribution advantage, the use of protons in cancer treatment has expanded greatly in recent years. In addition to the physical dose distribution, ions heavier than protons have increased biological advantages because of greater cell killing, decreased oxygen effect and smaller variation in radiation sensitivity through the cell cycle in replicating cells. Many of these biological advantages were demonstrated originally in the US and the early clinical studies of heavy ions were in the US. This knowledge led to development of five carbon ion therapy centers overseas, but there are none in the US. Importantly, many critical biology and physics questions remain about particles for therapy use, and this paucity of data is a significant impediment to exploiting the full potental of charged particle therapy. In anticipation that, in the not-too-distant future, therapy with ions heavier than protons will be resurrected in the US, fundamental radiation biology studies are proposed herein that will provide new data needed to guide R&D for such a facility. The proposed studies will utilize the unique facilities at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), currently the only location in the US where biological studies with ions heavier than protons can be conducted, to perform specific, highly clinically-relevant, cutting-edge studies. The overall goal is to address whether carbon is the optimal ion species for cancer therapy with particles and what tumor characteristics should be used to identify the tumors that would benefit most from ion therapy. The specific aims are to: (1) determine biological effectiveness of several ion species (atomic numbers from helium to oxygen) of clinical interest compared to 200 MeV protons as a function of depth in tissue equivalent material for selected tumor and normal cell types of varying radiation responsiveness and (2) assess the mode of cell death (apoptosis, permanent cell cycle arrest, mitotic catastrophe, autophagy) in cells irradiated with heavier ions compared to protons. We will test the hypothesis that the greater effectiveness of heavy ion-induced cell killing for cell types that show greater cell recovery after low LET radiations (i.e., low / ratios) results from increased induction of apoptosis in cells that are normally resistant to low LET-radiation-induced apoptosis. This systematic study will provide novel information on which ion species might be most useful for therapy, increase insight into which specific tumor types might be best treated with specific ions, and provide quantitative data to facilitate novel biophysical modeling of ion beams for therapy. This information will help guide planning for a heavier-than-protons facility in the US.